2014
Leurs, Ulrike; Lohse, Brian; Rand, Kasper D; Ming, Shonoi; Riise, Erik S; Cole, Philip A; Kristensen, Jesper L; Clausen, Rasmus P
Substrate- and cofactor-independent inhibition of histone demethylase KDM4C Journal Article
In: ACS Chem Biol, vol. 9, no. 9, pp. 2131-8, 2014, ISSN: 1554-8937.
Abstract | Links | BibTeX | Tags: Amino Acid Sequence, Catalytic Domain, Cell Line, Coenzymes, Deuterium Exchange Measurement, Enzyme Inhibitors, High-Throughput Screening Assays, Histone Demethylases, Humans, Inhibitory Concentration 50, Jumonji Domain-Containing Histone Demethylases, Molecular Sequence Data, Peptide Library
@article{1299981,
title = {Substrate- and cofactor-independent inhibition of histone demethylase KDM4C},
author = {Ulrike Leurs and Brian Lohse and Kasper D Rand and Shonoi Ming and Erik S Riise and Philip A Cole and Jesper L Kristensen and Rasmus P Clausen},
doi = {10.1021/cb500374f},
issn = {1554-8937},
year = {2014},
date = {2014-09-01},
journal = {ACS Chem Biol},
volume = {9},
number = {9},
pages = {2131-8},
abstract = {Inhibition of histone demethylases has within recent years advanced into a new strategy for treating cancer and other diseases. Targeting specific histone demethylases can be challenging, as the active sites of KDM1A-B and KDM4A-D histone demethylases are highly conserved. Most inhibitors developed up-to-date target either the cofactor- or substrate-binding sites of these enzymes, resulting in a lack of selectivity and off-target effects. This study describes the discovery of the first peptide-based inhibitors of KDM4 histone demethylases that do not share the histone peptide sequence or inhibit through substrate competition. Through screening of DNA-encoded peptide libraries against KDM1 and -4 histone demethylases by phage display, two cyclic peptides targeting the histone demethylase KDM4C were identified and developed as inhibitors by amino acid replacement, truncation, and chemical modifications. Hydrogen/deuterium exchange mass spectrometry revealed that the peptide-based inhibitors target KDM4C through substrate-independent interactions located on the surface remote from the active site within less conserved regions of KDM4C. The sites discovered in this study provide a new approach of targeting KDM4C through substrate- and cofactor-independent interactions and may be further explored to develop potent selective inhibitors and biological probes for the KDM4 family.},
keywords = {Amino Acid Sequence, Catalytic Domain, Cell Line, Coenzymes, Deuterium Exchange Measurement, Enzyme Inhibitors, High-Throughput Screening Assays, Histone Demethylases, Humans, Inhibitory Concentration 50, Jumonji Domain-Containing Histone Demethylases, Molecular Sequence Data, Peptide Library},
pubstate = {published},
tppubtype = {article}
}
Inhibition of histone demethylases has within recent years advanced into a new strategy for treating cancer and other diseases. Targeting specific histone demethylases can be challenging, as the active sites of KDM1A-B and KDM4A-D histone demethylases are highly conserved. Most inhibitors developed up-to-date target either the cofactor- or substrate-binding sites of these enzymes, resulting in a lack of selectivity and off-target effects. This study describes the discovery of the first peptide-based inhibitors of KDM4 histone demethylases that do not share the histone peptide sequence or inhibit through substrate competition. Through screening of DNA-encoded peptide libraries against KDM1 and -4 histone demethylases by phage display, two cyclic peptides targeting the histone demethylase KDM4C were identified and developed as inhibitors by amino acid replacement, truncation, and chemical modifications. Hydrogen/deuterium exchange mass spectrometry revealed that the peptide-based inhibitors target KDM4C through substrate-independent interactions located on the surface remote from the active site within less conserved regions of KDM4C. The sites discovered in this study provide a new approach of targeting KDM4C through substrate- and cofactor-independent interactions and may be further explored to develop potent selective inhibitors and biological probes for the KDM4 family.